OP0102 IDENTIFICATION OF NEW RISK LOCI AND PATHWAYS INVOLVED IN GCA PATHOGENESIS BY A GENOME-WIDE STUDY
Authors: G. Borrego-Yaniz, L. Ortiz-Fernández, M. Kerick, A. Madrid-Paredes, A. Vaglio, J. Hernández-Rodríguez, S. Mackie, S. Castañeda, R. Solans-Laqué, J. Mestre, B. Dasgupta, R. Watts, N. Khalidi, C. Langford, S. R. Ytterberg, L. Beretta, M. Govoni, G. Emmi, M. A. Cimmino, T. Witte, T. Neumann, J. Holle, V. Schönau, G. Pugnet, T. Papo, J. Haroche, A. Mahr, L. Mouthon, Ø. Molberg, A. Diamantopoulos, A. Voskuyl, T. Daikeler, C. Berger, E. Molloy, D. Blockmans, U. G. Consortium, I. Gca Consortium, N. Ortego, E. Brouwer, P. Lamprecht, S. Klapa, C. Salvarani, P. A. Merkel, M. C. Cid, M. A. González-Gay, A. Morgan, J. Martin Ibanez, A. Márquez
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Giant cell arteritis (GCA) is a chronic large-vessel vasculitis that affects mainly the aorta and its primary branches, and in Western countries is the most common form of vasculitis in people older than 50 years. The most severe manifestations of GCA include blindness and ischemic stroke caused by occlusion of affected arteries. GCA presents a complex aetiology whose genetic component remains largely unknown. Currently, options for both diagnosis and treatment for this pathology are limited, highlighting the need to better understand the genetic factors involved in susceptibility to GCA. <h3>Objectives</h3> The main goal of this study was to characterise the genetic basis of GCA by performing the largest genome-wide association study (GWAS) in this vasculitis to date. <h3>Methods</h3> A total of 3,498 GCA patients with GCA and 15,550 healthy individuals from ten populations of European ancestry were included in this study. After strict quality controls and imputation, 6,691,294 genetic variants were analysed by logistic regression using the first 10 principal components and sex as covariates. Loci showing a significant (p&lt;5E-8) or suggestive (p&lt;5E-5) association with the disease were selected for functional <i>in silico</i> analyses, including causal gene prioritisation with FUMA, enrichment of functional annotations of cell-specific histone marks using GoShifter. Finally, we performed a drug repurposing analysis, by evaluating the proposed mapped genes of the significant loci as targets for approved drug using the DrugBank database, and developed a polygenic risk score (PRS) for GCA susceptibility prediction. <h3>Results</h3> Three risk loci for GCA not previously reported were identified, two of them located in genes related to the vascular endothelial growth factor (VEGF) pathway: <i>MFGE8</i> (rs8029053, p=4.96E-8, OR=1.19), encoding lactadherin, and <i>VTN</i> (rs704, p=2.75E-9, OR=0.84)], encoding vitronectin; and the third one located in the gene <i>CCDC25</i> (rs11782624, p=1.28E-8, OR=1,18), that codifies a receptor of neutrophil extracellular traps (NETs). Additionally, we replicated the associations previously described within the HLA region and the <i>PLG</i> gene, which is also involved in angiogenesis. The results of the functional annotation showed that the GCA-associated loci act as regulatory variants influencing gene expression in vascular tissue and immune cell types. Furthermore, we also found a significant enrichment in histone marks in several immune cell types, especially in natural killer cells. The results of the drug repurposing analysis suggest abciximab, an antagonist of the vitronectin protein and approved for the treatment of acute coronary syndrome, as a potential candidate to treat GCA. Finally, the PRS model was best defined by including 28 genetic variants, being capable of identifying a fraction of individuals with more than three times the risk of developing GCA (OR=3.1 [2.1-4.7], p=1.71E-8). <h3>Conclusion</h3> Through the largest genomic study performed in GCA to date, we identified three genetic regions associated with this vasculitis that were not previously reported. These results also identified new physiological pathways and cell types potentially relevant to the development of the disease. These results allowed us to establish a prediction tool for identifying individuals at high-risk for developing GCA and also to propose further investigation of abciximab, a drug that could be potentially repurposed for treatment of GCA. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.